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Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)
  1. Santhosh Dhanraj1,2,
  2. Sethu Madhava Rao Gunja3,
  3. Adam P Deveau4,
  4. Mikael Nissbeck3,
  5. Boonchai Boonyawat1,5,
  6. Andrew J Coombs6,
  7. Alessandra Renieri7,
  8. Mafalda Mucciolo8,
  9. Annabella Marozza8,
  10. Sabrina Buoni9,
  11. Lesley Turner10,
  12. Hongbing Li1,
  13. Ameer Jarrar6,
  14. Mathura Sabanayagam1,
  15. Melanie Kirby5,
  16. Mary Shago11,
  17. Dalila Pinto1,12,
  18. Jason N Berman4,6,
  19. Stephen W Scherer1,13,
  20. Anders Virtanen3,
  21. Yigal Dror1,2,5
  1. 1Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
  3. 3Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
  4. 4Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
  5. 5Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
  6. 6Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada
  7. 7Department of Medical Genetics, University of Siena, Siena, Italy
  8. 8Genetica Medica, Azienda Ospedaliera Universitaria, Senese, Siena, Italy
  9. 9Neuropsichiatria Infantile, Azienda Ospedaliera, Universitaria Senese, Siena, Italy
  10. 10Department of Discipline of Genetics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
  11. 11Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
  12. 12Departments of Psychiatry, and Genetics and Genomic Sciences, Seaver Autism Center, The Mindich Child Health & Development Institute, Mount Sinai School of Medicine, New York, New York, USA
  13. 13Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  1. Correspondence to Dr Yigal Dror, Division of Hematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8; yigal.dror{at}


Background Deadenylation regulates RNA function and fate. Poly(A)-specific ribonuclease (PARN) is a deadenylase that processes mRNAs and non-coding RNA. Little is known about the biological significance of germline mutations in PARN.

Methods We identified mutations in PARN in patients with haematological and neurological manifestations. Genomic, biochemical and knockdown experiments in human marrow cells and in zebrafish have been performed to clarify the role of PARN in the human disease.

Results We identified large monoallelic deletions in PARN in four patients with developmental delay or mental illness. One patient in particular had a severe neurological phenotype, central hypomyelination and bone marrow failure. This patient had an additional missense mutation on the non-deleted allele and severely reduced PARN protein and deadenylation activity. Cells from this patient had impaired oligoadenylation of specific H/ACA box small nucleolar RNAs. Importantly, PARN-deficient patient cells manifested short telomeres and an aberrant ribosome profile similar to those described in some variants of dyskeratosis congenita. Knocking down PARN in human marrow cells and zebrafish impaired haematopoiesis, providing further evidence for a causal link with the human disease.

Conclusions Large monoallelic mutations of PARN can cause developmental/mental illness. Biallelic PARN mutations cause severe bone marrow failure and central hypomyelination.

  • Genetics
  • Haematology (incl Blood transfusion)
  • Copy-number
  • Molecular genetics
  • Neurology

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